AMG 479, a fully human anti–insulin-like growth factor receptor type I monoclonal antibody, inhibits the growth and survival of pancreatic carcinoma cells

Beltran, Pedro J.; Mitchell, Petia; Chung, Young-A; Cajulis, Elaina; Lu, John; Belmontes, Brian; Ho, Joanne; Tsai, Mei Mei; Zhu, Min; Vonderfecht, Steven; Baserga, Renato; Kendall, Richard; Radinsky, Robert; Calzone, Frank J.

doi:10.1158/1535-7163.mct-08-1171

Cited by 119 publications

(97 citation statements)

References 29 publications

(30 reference statements)

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“…For instance, ganitumab, aflibercept, and exatecan reportedly induce strong anticancer effects without severe side effects in preclinical mouse models. However, the agents could not show the similar effect in human cancer patients during clinical trials (11,23,24). Our model accurately mimics the action of gemcitabine in human pancreatic cancers.…”

Section: Discussionmentioning

confidence: 91%

Investigation into metastatic processes and the therapeutic effects of gemcitabine on human pancreatic cancer using an orthotopic SUIT‑2 pancreatic cancer mouse model

et al. 2017

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Abstract. Prognosis of pancreatic cancer is poor, thus the development of novel therapeutic drugs is necessary. During preclinical studies, appropriate models are essential for evaluating drug efficacy. The present study sought to determine the ideal pancreatic cancer mouse model for reliable preclinical testing. Such a model could accurately reflect human pancreatic cancer phenotypes and predict future clinical trial results. Systemic pathology analysis was performed in an orthotopic transplantation model to prepare model mice for use in preclinical studies, mimicking the progress of human pancreatic cancer. The location and the timing of inoculated cancer cell metastases, pathogenesis and cause of fatality were analyzed. Furthermore, the efficacy of gemcitabine, a key pancreatic cancer drug, was evaluated in this model where liver metastasis and peritoneal dissemination occur. Results indicated that the SUIT-2 orthotopic pancreatic cancer model was similar to the phenotypic sequential progression of human pancreatic cancer, with extra-pancreatic invasion, intra-peritoneal dissemination and other hematogenous organ metastases. Notably, survival was prolonged by administering gemcitabine to mice with metastasized pancreatic cancer. Furthermore, the detailed effects of gemcitabine on the primary tumor and metastatic tumor lesions were pathologically evaluated in mice. The present study indicated the model accurately depicted pancreatic cancer development and metastasis. Furthermore, the detailed effects of pancreatic cancer drugs on the primary tumor and on metastatic tumor lesions. We present this model as a potential new standard for new drug development in pancreatic cancer.

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Section: Discussionmentioning

confidence: 91%

Investigation into metastatic processes and the therapeutic effects of gemcitabine on human pancreatic cancer using an orthotopic SUIT‑2 pancreatic cancer mouse model

et al. 2017

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“…IGF-1R shares significant structural homology with IR, and targeting IGF pathway with IGF-1R inhibitor antibodies is sensible as it only blocks IGF-1R induced mitogenic signaling but is not affecting IR signaling, which could lead to dysregulation of glucose homeostasis [20, 21]. IGF-1R antibodies demonstrated clinical activity in phase 2 studies in small number of patients with select tumor types including Ewing sarcoma, thymoma and thymic carcinoma [22–24].…”

Section: Introductionmentioning

confidence: 99%

Augmentation of response to nab-paclitaxel by inhibition of insulin-like growth factor (IGF) signaling in preclinical pancreatic cancer models

et al. 2016

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Nab-paclitaxel has recently shown greater efficacy in pancreatic ductal adenocarcinoma (PDAC). Insulin like growth factor (IGF) signaling proteins are frequently overexpressed in PDAC and correlate with aggressive tumor phenotype and poor prognosis. We evaluated the improvement in nab-paclitaxel response by addition of BMS-754807, a small molecule inhibitor of IGF-1R/IR signaling, in preclinical PDAC models. In subcutaneous xenografts using AsPC-1 cells, average net tumor growth in different therapy groups was 248.3 mm3 in controls, 42.4 mm3 after nab-paclitaxel (p = 0.002), 93.3 mm3 after BMS-754807 (p = 0.01) and 1.9 mm3 after nab-paclitaxel plus BMS-754807 (p = 0.0002). In subcutaneous xenografts using Panc-1 cells, average net tumor growth in different therapy groups was: 294.3 mm3 in controls, 23.1 mm3 after nab-paclitaxel (p = 0.002), 118.2 mm3 after BMS-754807 (p = 0.02) and −87.4 mm3 (tumor regression) after nab-paclitaxel plus BMS-754807 (p = 0.0001). In peritoneal dissemination model using AsPC-1 cells, median animal survival was increased compared to controls (21 days) after therapy with nab-paclitaxel (40 days, a 90% increase, p = 0.002), BMS-754807 (27 days, a 29% increase, p = 0.01) and nab-paclitaxel plus BMS-754807 (47 days, a 124% increase, p = 0.005), respectively. Decrease in proliferation and increase in apoptosis by nab-paclitaxel and BMS-754807 therapy correlated with their in vivo antitumor activity. In vitro analysis revealed that the addition of IC25 dose of BMS-754807 decreased the nab-paclitaxel IC50 of PDAC cell lines. BMS-754807 therapy decreased phospho-IGF-1R/IR and phospho-AKT expression, and increased cleavage of caspase-3 and PARP-1. These results support the potential of BMS-754807 in combination with nab-paclitaxel as an effective targeting option for pancreatic cancer therapy.

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“…A growing number of therapeutic agents targeting IGF-IR, including mAbs and small-molecule kinase inhibitors, have been developed for cancer therapy and have shown preclinical antitumor efficacy (26)(27)(28)(29)(30)(31)(32). Many of these IGF-IR inhibitors are being clinically evaluated in multiple tumor indications as single agents or in combination with other therapeutic agents, and some have shown encouraging clinical responses (32)(33)(34).…”

Section: Introductionmentioning

confidence: 99%

Combination of Two Insulin-Like Growth Factor-I Receptor Inhibitory Antibodies Targeting Distinct Epitopes Leads to an Enhanced Antitumor Response

Dong

Demarest

Sereno

et al. 2010

Molecular Cancer Therapeutics

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The insulin-like growth factor-I receptor (IGF-IR) is a cell surface receptor tyrosine kinase that mediates cell survival signaling and supports tumor progression in multiple tumor types. We identified a spectrum of inhibitory IGF-IR antibodies with diverse binding epitopes and ligand-blocking properties. By binding distinct inhibitory epitopes, two of these antibodies, BIIB4 and BIIB5, block both IGF-I and IGF-II binding to IGF-IR using competitive and allosteric mechanisms, respectively. Here, we explored the inhibitory effects of combining BIIB4 and BIIB5. In biochemical assays, the combination of BIIB4 and BIIB5 improved both the potency and extent of IGF-I and IGF-II blockade compared with either antibody alone. In tumor cells, the combination of BIIB4 and BIIB5 accelerated IGF-IR downregulation and more efficiently inhibited IGF-IR activation as well as downstream signaling, particularly AKT phosphorylation. In several carcinoma cell lines, the antibody combination more effectively inhibited ligand-driven cell growth than either BIIB4 or BIIB5 alone. Notably, the enhanced tumor growth-inhibitory activity of the BIIB4 and BIIB5 combination was much more pronounced at high ligand concentrations, where the individual antibodies exhibited substantially reduced activity. Compared with single antibodies, the BIIB4 and BIIB5 combination also significantly further enhanced the antitumor activity of the epidermal growth factor receptor inhibitor erlotinib and the mTOR inhibitor rapamycin. Moreover, in osteosarcoma and hepatocellular carcinoma xenograft models, the BIIB4 and BIIB5 combination significantly reduced tumor growth to a greater degree than each single antibody. Taken together, our results suggest that targeting multiple distinct inhibitory epitopes on IGF-IR may be a more effective strategy of affecting the IGF-IR pathway in cancer. Mol Cancer Ther; 9(9); 2593-604. ©2010 AACR.

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AMG 479, a fully human anti–insulin-like growth factor receptor type I monoclonal antibody, inhibits the growth and survival of pancreatic carcinoma cells

Abstract: Pancreatic carcinoma is a leading cause of cancer deaths, and recent clinical trials of a number of oncology therapeutics have not substantially improved clinical outcomes.

Cited by 119 publications

References 29 publications

Investigation into metastatic processes and the therapeutic effects of gemcitabine on human pancreatic cancer using an orthotopic SUIT‑2 pancreatic cancer mouse model

Investigation into metastatic processes and the therapeutic effects of gemcitabine on human pancreatic cancer using an orthotopic SUIT‑2 pancreatic cancer mouse model

Augmentation of response to nab-paclitaxel by inhibition of insulin-like growth factor (IGF) signaling in preclinical pancreatic cancer models

Combination of Two Insulin-Like Growth Factor-I Receptor Inhibitory Antibodies Targeting Distinct Epitopes Leads to an Enhanced Antitumor Response

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